What is hypercalcemia and how is it managed?

Hypercalcemia: Diagnosis, Monitoring, and Management

Hypercalcemia is a potentially life-threatening condition characterized by elevated serum calcium levels that requires systematic monitoring of calcium, parathyroid hormone, magnesium, phosphorus, and renal function to prevent serious complications including cardiac arrhythmias, seizures, and renal failure. 1

Definition and Classification

Hypercalcemia is defined as an elevated serum calcium level above the normal range, typically:

• Mild: Total calcium <12 mg/dL (<3 mmol/L)
• Moderate: Total calcium 12-14 mg/dL (3-3.5 mmol/L)
• Severe: Total calcium ≥14 mg/dL (≥3.5 mmol/L)

Pathophysiology

Hypercalcemia results from one of three primary mechanisms:

1. Increased bone resorption: Most common mechanism in malignancy and hyperparathyroidism
2. Increased intestinal calcium absorption: Seen in vitamin D toxicity and granulomatous disorders
3. Decreased renal calcium excretion: Occurs in thiazide use, familial hypocalciuric hypercalcemia

Excessive release of calcium into the bloodstream as bone is resorbed leads to:

• Polyuria and gastrointestinal disturbances
• Progressive dehydration
• Decreasing glomerular filtration rate
• Increased renal resorption of calcium
• Cycle of worsening systemic hypercalcemia 2

Clinical Manifestations

Hypercalcemia can affect multiple organ systems:

• Neurological: Fatigue, irritability, confusion, somnolence, coma, seizures, abnormal involuntary movements 3, 1
• Gastrointestinal: Nausea, vomiting, constipation, abdominal pain
• Renal: Polyuria, polydipsia, nephrocalcinosis, renal failure
• Cardiovascular: QT interval prolongation, cardiac arrhythmias, hypertension, cardiomyopathy 3
• Musculoskeletal: Bone pain, osteopenia/osteoporosis, muscle weakness 1

Etiology

The most common causes of hypercalcemia (>90% of cases) are:

1. Primary hyperparathyroidism
2. Malignancy-associated hypercalcemia 4

Other causes include:

• Granulomatous disorders (sarcoidosis)
• Medications (thiazide diuretics, lithium, vitamin A/D excess)
• Endocrinopathies (thyrotoxicosis, adrenal insufficiency)
• Immobilization
• Familial hypocalciuric hypercalcemia
• Milk-alkali syndrome

Diagnostic Approach

Laboratory Evaluation

The following tests should be performed in patients with suspected hypercalcemia:

• Total serum calcium
• Albumin (for corrected calcium calculation)
• Intact parathyroid hormone (iPTH)
• Parathyroid hormone-related protein (PTHrP) if malignancy suspected
• Vitamin D metabolites (25-OH and 1,25-OH₂)
• Phosphorus
• Magnesium
• Renal function tests
• Thyroid-stimulating hormone (TSH) 1

Critical Calculation

Always correct calcium for albumin using the formula:

• Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 - Serum albumin (g/dL)] 1, 2

Diagnostic Pearls

• Elevated/normal PTH with hypercalcemia suggests primary hyperparathyroidism
• Suppressed PTH (<20 pg/mL) indicates non-PTH mediated causes like malignancy 4
• Ionized calcium is the most accurate measurement but not always readily available 2

Monitoring Requirements

Regular monitoring is essential for patients with hypercalcemia:

1. Baseline and periodic assessment:

   • Serum calcium (total and ionized if available)
   • Parathyroid hormone
   • Magnesium
   • Phosphorus
   • Renal function (creatinine, GFR)
   • Electrocardiogram (for QT interval) 3, 1

2. Targeted calcium monitoring during high-risk periods:

   • Perioperatively
   • During acute illness
   • Perinatally
   • During pregnancy 3

3. Bone health monitoring:

   • Bone mineral density testing
   • Assessment for osteopenia/osteoporosis 3, 1

Management Approach

Immediate Management of Severe Hypercalcemia

1. Hydration: Aggressive IV fluid resuscitation with normal saline to restore volume and enhance calcium excretion 1, 4

2. Loop diuretics: After adequate hydration, to enhance calcium excretion (but only after volume restoration) 1

3. Bisphosphonates: First-line pharmacologic therapy

   • Zoledronic acid: 4 mg IV over 15 minutes (preferred for malignancy-associated hypercalcemia)
   • Pamidronate: 90 mg IV over 2 hours as an alternative 1, 2

4. Calcitonin: For immediate short-term management of severe symptomatic hypercalcemia 5

5. Denosumab: For hypercalcemia refractory to bisphosphonates or in patients with severe renal impairment 1

6. Glucocorticoids: For hypercalcemia due to vitamin D toxicity, granulomatous disorders, or some lymphomas 1

7. Dialysis: Reserved for severe hypercalcemia complicated by renal failure 5

Long-term Management

1. Treatment of underlying cause:

   • Parathyroidectomy for appropriate cases of primary hyperparathyroidism
   • Anti-tumor therapy for malignancy-associated hypercalcemia
   • Discontinuation of offending medications 1

2. Ongoing monitoring of serum calcium, phosphate, magnesium, and renal function 1

3. Vitamin D supplementation may be required in certain cases, but must be carefully monitored 3

Pitfalls to Avoid

1. Failing to correct calcium for albumin: May lead to missed diagnosis or inaccurate assessment of severity 1

2. Inadequate hydration before bisphosphonate administration: Can worsen renal function 1

3. Not monitoring for hypocalcemia after treatment: Especially with denosumab 1

4. Treating the laboratory value without addressing underlying cause: Critical to identify and treat the primary etiology 1

5. Overlooking renal function when dosing bisphosphonates: Dose adjustment needed in renal impairment 1

6. Delaying treatment of severe hypercalcemia: Should not wait for complete diagnostic workup before initiating treatment 1

7. Overcorrection leading to iatrogenic hypercalcemia: Can result from dehydration or treatment compliance changes 3

By systematically addressing hypercalcemia with appropriate monitoring and treatment, clinicians can effectively manage this potentially dangerous condition and prevent serious complications that affect morbidity, mortality, and quality of life.